Project Summary Diabetic retinopathy (DR) is a leading cause of vision loss, affecting nearly 100 million people worldwide. Vascular leakage factors and angiogenic factors play an important role in the pathogenesis of vision-threatening diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR), respectively. Vascular endothelial growth factor (VEGF) inhibitors have been approved for DME but not PDR with limited therapeutic efficacy. Identification of additional pathological ligands may lead to development of novel therapies for DME and PDR. We recently discovered secretogranin III (Scg3) as a highly disease-associated pro-angiogenic factor that preferentially binds to and stimulates angiogenesis of diabetic but not normal vessels. In contrast, VEGF binds to and induces angiogenesis of both diabetic and normal vessels. Among thousands of quantified endothelial ligands, Scg3 has the highest binding activity ratio to diabetic vs. control retinal vessels but the lowest binding to normal vasculature. Unlike VEGF upregulation in PDR, however, Scg3 expression minimally increases in diabetic retina. This project is to investigate a new pathogenic mechanism by which the upregulation of Scg3 selective binding to diseased vessels, but not ligand expression itself, exacerbates DR pathogenesis. In Aim 1, we will quantify and correlate Scg3 disease-related endothelial binding activity to the severity of DR leakage. In Aim 2, we will establish a correlation between Scg3 endothelial binding activity and the severity of pathological retinal neovascularization in mice. In Aim 3, a well-characterized Scg3-neutralizing monoclonal antibody with high therapeutic efficacy and safety will be humanized and analyzed for its activity to alleviate DR leakage and pathological retinal neovascularization. To our knowledge, Scg3 is the first highly selective angiogenic factor. Investigation of Scg3 and its pathogenic mechanism will facilitate the discovery and characterization of other ligands with similar disease selectivity. Humanization of anti-Scg3 antibody may lead to the development of a new class of ?selective angiogenesis blockers? for the therapy of DR and other retinal vascular diseases.